Bromosteroids



Patented Get. 5, 1954 BROMO STEROIDS Robert Bruce Moffett, Kalamazoo,Mich., assignor to The Upjohn Company, Kalamazoo, Mich., a

corporation of Michigan No Drawing. Application March 21, 1952, SerialNo. 277,911

13 Claims. 1

This invention relates to novel bromosteroids and is more particularlyconcerned with novel 3- acyloxy-l6(l7)-oxido 21 bromopregnane 20- onesand to a novel process for the production thereof.

The novel compounds of the present invention are the normal andallo-3acy1oxy-l6(1'l)- oxido-21-bromopregnane 20 ones wherein theacyloxy groups have the formula AcO, Ac being the acyl radical of anorganic carboxylic acid. These compounds may be represented by thefollowing formula:

It is an object of the present invention to provide novel allo andnormal 3-acyloxy-l6(l7) oXido-Zl-bromopregnane20-ones. It is anotherobject to provide a novel process for the production thereof. Otherobjects of the invention will be apparent to those skilled in the art towhich this invention pertains.

The compounds of the present invention have utility in the production ofknown and new steroids having an oxygen atom at carbon atoms 17, 20, and21, said compounds being members AeO of a class of compounds possessingknown physicompound which then loses the 20-bromine atom and the acylradical of the 20-acyloxy group to produce a 20-ketone group, therebygiving a desired 3-acyloxy-16 (1'7) -oxido-21-bromopregnane- 20-one.When following the method of the present invention, high yields of thedesired S-acyl- 2 oxy-16(1'7) -oxido-21-br0mopregnane-20-one arconsistently obtained with the yield and the time required forcompletion of reaction being somewhat dependent upon the temperature atwhich the reaction is carried out and the amount of bromine used. Thebest yields are usually obtained when the reaction is carried out attemperatures below room temperature and about a molar equivalent ofbromine is employed.

The starting compounds for the method of the present invention areprepared by reacting a 30:- or 3 8-hydroxy or acyloxy-16-pregnene-20-onewith isopropenyl acetate or other isopropenyl acylate such as, forexample, isopropenyl propionate, butyrate, octanoate, benzoate, or thelike, in the presence of an acid catalyst such as, for example,para-toluenesulfonic acid, sulfoacetic acid, sulfosalicylic acid, or thelike, and thereafter reacting the thus-produced 3,20-diacyloxy-16,20-pregnadiene with about a molar equivalent of a peracid such as,for example, perbenzoic acid or peracetic acid in a solvent such as, forexample, methylene chloride, benzene, toluene, acetic acid, mixtures ofthese, and others. Conveniently, the products of the present inventioncan be prepared from the corresponding 3-hydroxy or 3-acyloxy-l6--pregnene 2'0 one Without isolating the intermediatecompounds. For instance, treating 3,3-acetoxy-IG-pregnene-ZO-one withisopropenyl acetate in the presence of para-toluenesulfonic acid,removing the excess isopropenyl acetate, dissolving the residue inmethylene chloride and cooling, followed by the successive addition ofabout one molar equivalent of peracetic acid and bromine is productiveof 3 8-acetoxy- 16(17) -oxido-2l-bromopregnane-20-one.

The following examples are illustrative of the process and products ofthe present invention but are not to be construed as limiting.

Example 1.-3B,20-diac etoxy16,20-allopregnadiene Two grams ofBB-acetoxy-lfi-allopregnene-ZO- one [Marker et al., J. Am. Chem. Soc.,64, 468 (1942) l, twenty milliliters of isopropenyl acetate and 0.1 gramof para-toluenesulfonic acid were placed in a reaction flask to whichwas attached a short fractionating column. The mixture was heated toboiling and a mixture of acetone and isopropenyl acetate distillingbetween 56 and ninety degrees centigrade was collected over a period offrom about eight to ten hours. The para-toluenesulfonic acid was thenneutralized by addition of solid sodium bicarbonate and the excessisopropenyl acetate was thereafter removed under reduced pressure. Coldwater and methylene chloride were added with stirring to the residue.The methylene chloride layer was separated, washed with water, driedover anhydrous sodium sulfate and the solvent then removed bydistillation. The residue, on crystallization from acetone, gave 1.4grams'of 3,9,20-diacetoxy-16,20- allopregnadiene which melted at 143 to145 degrees centigrade and had an [111 of plus ten degrees (0.979percent in chloroform).

Example 2 .--3p,20-diaceto:cy-16 (1 7 -orz'do- 20- allopregnene Asolution of 1.2 grams (0.003 mole) of 3,6,20-diacetoxy-16,20-a1lopregnadiene in ten milliliters of chloroform and tenmilliliters .of benzene was cooled in an ice and salt bath and 4.15milliliters (00.4 mole) of a 1.93 normal benzene solution of perbenzoicacid was then added thereto. The reaction mixture was maintained atabout zero degrees'centigrade for sixteen hours, whereafter the solutionwas diluted with etherand washed with an ice-cold dilute sodiumcarbonate solution. The ether solution Was-then washed with two portionsof water and then with a saturated salt solution and thereafter driedwith anhydrous sodium sulfate. The solvent wasthen'removed under reducedpressure and the residue recrystallized from vSkellysolve B (hexanehydrocarbons) to yield 0.95 gram of product melting at 127 to129'degrees centigrade. Recrystallization of these crystals from thesame solvent was productive of 3p,20-diacetoxy-16(17) -oxido 20allopregnen'e, melting at 128 to 131 degrees centigrade, and having an[111 of plus thirty degrees (0.589 percent in chloroform). Infrared andultraviolet absorption analyses confirmed the structure.

AnaZysis.Percent calculated for C25H36051 C, '72.08';-H, 8.71; acetyl,20.66. Found: C, 71.96; H, 8.74; acetyl, 20.10.

Example 3.3p-aceto:cy-1 6 (17) -o:cz'do-21 bromoaZZopregnane-ZO-one Asolution of 0.416 gram (0.001 mole) of 313,20- diacetoxy 16(17) oxido 20allopregnene was cooled in an ice-salt bath to about minus ten degreescentigrade and 9.25 milliliters (0.001 mole) of a 0.216 normal methylenechloride solution of bromine was then added dropwise thereto, withstirring, during a period of one hour. The solvent was thereafterremoved at reduced pressure at a temperature below room temperature. Thewhite crystalline residue was crystallized from a mixture of acetone andpentane to produce product melting at 184 to 187 degrees centigrade.Recrystallization of these crystals from acetone gave 3 3-acetoxy-l6(17)-oxido-2l-bromoallopregnane-20-one, melting at 188 to 190 degreescentigrade and having an [M of plus 45 degrees (0.819 percent inchloroform) Infrared spectrum was consistent with the theoreticalstructure.

Analysis.-Percent calculated for C23Ha3B1'O4Z C, 60.92; H, 7.34; Br,17.63. Found: C, 60.91; H, 7.27; Br, 17.99.

The structure of the thus-produced 3 8-acetoxy- 16(1'7)oxide-2l-bromoallopregnane-ZO-one was confirmed by conversion to theknown 3 8,21-diacetoxy-16(l'7)-oxidoallopregnane-20-one in the followingmanner: A mixture of 0.2 gram of the above-obtained 3/3-acetoxy-16(17)-oxido-2l-bromoallopregnane-ZO-one, 0.15 gram of powdered sodium iodide,and ten milliliters of acetone was refluxed for fifteen minutes and thenfiltered. There was then added to the filtrate 1.5 grams of postassiumbicarbonate and 0.9 milliliter of acetic acid, whereafter the mixturewas refluxed with stirring for twelve hours. The whole was then dilutedwith water and extracted with ether. The ether solution was successivelywashed with a cold dilute sodium thiosulfate solution, water, and asaturated sodium chloride solution, and thereafter dried with anhydroussodium sulfate. The solvent was then removed under reduced pressure andthe residue crystallized from methanol to yield 0.12 grams of whitecrystalline product melting at to 148 degrees centigrade.Recrystallization of these crystals from a mixture of acetone andpentane produced 3,8,21-diacetoxy- 16(17)-oxidoallopregnane-20-one,which melted at 151 to 1525 degrees Centigrade.

Additional illustrations of the scope of the present invention are asfollows:

In the manner given in the preceding examples, 3,8 acetoxy 16(17)oxido-21-bromopregnane- 20-one is prepared by reacting 3,6,20-diacetoxy-16(1'7) oxido 20 pregnene with about 'one molar equivalent -of bromine.The 313,20 :-diacetoxy 16(17) oxido 20 pregnene is prepared by reacting35,20diacetoxy-l6,20-pregnadiene with apout one molar equivalent ofperbenzoic acid in benzene. The 35,20-diacetoxy- 16,20-pregnadiene isprepared by reacting -35- hydroxyor 3,8-acetoxy-16-pregnene-20-one withisopropenyl acetate in the presence of :paratoluenesulfonic acid.

In the manner given in the preceding examples, 3a-acetoxy-16 (17)-oxido-21 -bromoallopregnane- 20-one is prepared by reacting3a,20diacetoxy- 16(17) -oxido-20-allopregnene with about one molarequivalent of bromine. The 3a,20-diacetoxy- 16(17)-oxido-20-allopregneneis prepared by reacting 3a,20 diacetoxy 16,20 allopregnadiene with about1 molar equivalent of perbenzoic acid in benzene. The3oz,20-diacetoxy-16,20-allopregnadiene is preparedby reacting3a-hydroxyor 3u-acetoxy-16-a1lopregnene-20-one with isopropenyl acetatein the presence of para-toluenesulfonic acid.

Similarly, other 311- or 3,8-acyloxy-16(17) oxido-Zl-bromoallo andnormal pregnene-ZO-ones are prepared by reacting 3ozand3,9,20-diacyloxyl6( 17) -oxidoallo and normal -20-pregnenes with aboutone molar equivalent of bromine in a solvent such as, for example,methylene chloride, chloroform, benzene, toluene, acetic acid, mixturesof these, and others. The3,20-diacyl0xy 16(17)- oxidopregnenes areprepared by reacting 3,20- diacyloxy-16,20-pregnadienes with aboutonemolar equivalent of an organic peracid such as, for example, perbenzoicacid or peracetic acid, ina solvent such as above-named. The3,20-diacyloxy-16,20-pregnadienes are prepared by reacting a B-hydroxyor B-acyloxy allo or normalpregnane-20-one with isopropenyl acetate orother isopropenyl acylate inthe presence ofanacidic catalyst, such as,for example, para-toluenesulfonic acid, sulfoacetic acid,'sulfosalicylic acid, and others. Other isopropenyl acylates may-be usedin the method of the present. invention .but isopropenyl acetate ispreferredfor matters'of convenience and economy. When the :starting'compound is a 3-acyloxy-16-pregnene-20 one; the final product is notdependent upon the selected isopropenyl acylate, as the enol ester ofthe 20- keto group is subsequently removed upon bromination. The acyloxygroups of the abovenamed compounds are of the formula AcO, Ac being theacyl radical of acids such as, forexample, formic, acetic, propionic,butyric, valeric,

hexanoic, heptanoic, octanoic, benzoic, phenylacetic,cyclopentylcarboxylic, cyclohexylcarboxylie, and others, depending uponthe starting material and acylating agent used.

It is to be understood that the invention is not to be limited to theeXact details of operation of exact compounds shown and described asobvious modifications and equivalents will be apparent to one skilled inthe art and the invention is therefore to be limited only by the scopeof the appended claims,

I claim:

1. A 3-acyloXy-16(17) -oXido 21 bromopregnane--one wherein the acyloxygroup has the formula AcO, Ac being the acyl radical of a hydrocarboncarboxylic acid containing from one to eight carbon atoms, inclusive.

2. 3,3 acetoxy 16(17) oxido-21-bromopregnane-ZO-one.

3. 3B-acetoXy-l6(17) cXido-21-bromoallopregnane-20-one.

4. 3a acetoxy 16(17) oxido-Zl-bromopregnane-20-one.

5. A process for the production of a 3-acy1oXy- 16(17) -oxido 21bromopregnane-20-one which comprises: reacting a 3,20-diacyloXy-16(17)-oxid0-20-pregnene wherein the acyloxy groups have the formula AcO, Acbeing the acyl radical of an organic carboxylic acid, with about onemolar equivalent of bromine to produce a 3- acyloxy-16 17)-oXido-2l-bromopregnane-ZO-one.

6. A process for the production of 3,8-acetoxy- 16(17) -oxido 21bromopregnane-20-one which comprises: reacting 3fl,20-diacetoXy-16(l7)-oxido-20-pregnene with about one molar equivalent of bromine to produce3fi-ELCt0Xy-16(17)-OXld0- 21-bromopregnane-20-one.

7, A process for the production of BIB-acetoxy- 16(17) oxido 21bromoallopregnane 20 one which comprises: reacting 35,20 diacetoxy-16(17) -oxido-20-allopregnene with about one niolar equivalent ofbromine to produce 3,8-acetoxy- 16(17)-oxido-21-bromoallopregnane-20-one.

8. A process for the production of a 3-acyloxy- 16(17) -oxido 21bromopregnane-ZO-one which comprises: reacting a3,20-diacyioxy-16,20-pregnadiene, wherein the acyloxy groups have theformula AcO, Ac being the acyl radical of an organic carboXylic acidcontaining from one to eight carbon atoms, inclusive, with about one 4molar equivalent of an organic peracid at a temperature between aboutminus forty degrees centigrade and about forty degrees centigrade toproduce a 3,20-diacyloxy-l6(l7)-oXido-20-preg nene, and reacting thethus-produced 3,20-diacyloXy-16(l7) -0Xid0 2O pregnen-e with about onemolar equivalent of bromine to produce a 3-acyloxy-l6(17) -oxido 21bromopregnane-20- one.

9. A process for the production of 3,8-acetoxy- 16(17) -oxido 21bromopregnane-ZO-one which comprises: reacting35,20-diacetoxy-16,20-pregnadiene with about one molar equivalent of anorganic peracid at a temperature between about minus forty degreescentigrade and about forty degrees centigrade to produce3[3,20-diacetoxy- 16(17) -oxido-20-pregnene, and reacting thethusproduced 373,20 diacetoxy-16(l7) -oxido-20-pregnene with about onemolar equivalent of bromine to produce 35 acetoxy-16(17) -oxido-21-bromopregnane-ZO-one.

10. A process for the production of 3(3-acetoxy- 16(17)-oXido-21-bromoallopegnane-20one which comprises: reacting35,20-diacetoxy-l6,20-allopregnadiene with about one molar equivalent ofan organic peracid at a temperature between about minus forty degreescentigrade and about forty degrees centigrade to produce3,3,20-diacetoxy-16 (17) -oXido-20-allopregnene, and reacting thethus-produced 3,9,20-diacetoxy-16 l7) -oXido- 20-allopregnene with aboutone mol ar equivalent of bromine to produce 3p-acetoXy-'16(17)-oxido-21-bromoallopregnane-20-one.

11. A process for the production of a B-acyloxy- 16(17) -oxido 21bromopregnane-ZO-one which comprises: reacting a compound selected fromthe group consisting of 3-hydroxy-lfi-pregnene-ZO- ones and3-acyloxy-lfi-pregnene-ZO-ones, wherein the acyloxy groups have theformula A00, A0 being the acyl radical of an organic carboxylic acid,with an isopropenyl acylate in the presence of an acidic catalyst,reacting the thus-produced 3,20-diacyloXy-16,20-pregnadiene with aboutone molar equivalent of an organic peracid at a temperature betweenabout minus forty degrees centigrade and about forty degrees centigradeto produce a 3,20-diacyloxy-l6(17) -oxido20-pregnene, and reacting thethus-produced 3,20-diacyloxy-16(17) -oxido 20 pregnene with about onemolar equivalent of bromine to produce a 3- acyloxy-l6 (17)-oxido-2l-bromopregnane-20-one.

12. A process for the production of 3,8-acetoxy- 16(17) -oxido 21bromoallopregnane 20 one which comprises: reacting35-hydroxy-16-allopregnene-20-one with isopropenyl acetate in thepresence of an acidic catalyst, reacting the thusproduced 3 3,20diacetoxy-16,20-allopregnadiene with about one molar equivalent of anorganic peracid. at a temperature between about minus forty degreescentigrade and about forty degrees centigrade to produce3/3,20-diacetoXy-16(17)- oxido-ZO-allopregnene, and reacting thethusproduced 35,20 diacetoxy-l6(l7) -oxido-20-allopregnene with aboutone molar equivalent of bromine to produce 35-acetoxy-16(l7) -oxido-21-bromoallopregnane-ZO-one.

13. A process for the production of BB-acetoxy- 16(17) -oxido 21bromopregnane-ZO-one which comprises: reacting3e-hydroxy-l6-pregnene-20- me with isopropenyl acetate in the presenceof an acidic catalyst, reacting the thus-produced 36,20-diacetoxy-16,20-pregnadiene with about one molar equivalent of anorganic peracid at a temperature between about minus forty degreescentigrade and about forty degrees centigrade to produce 35,20diacetoxy-16(l7) -oXido-20-pregnene, and reacting the thus-produced35,20-diacetoxy-16( 17) -oXido-20-pregnene with about one molarequivalent of bromine to produce 35- acetoxy-16 (17)-oxido-2l-bromopregnane-20-one.

References Cited in the file of this patent UNITED STATES PATENTS NumberName Date 2,359,772 Marker Oct. 10, 1944 2,369,065 Marker Feb. 6, 19452,599,481 Plattner June 3, 1952

1. A 3-ACYLOXY-16(17)-OXIDO - 21 - BROMOPREGNANE-20-ONE WHEREIN THEACYLOXY GROUP HAS THE FORMULA ACO, AC BEING THE ACYL RADICAL OF AHYDROCARBON CARBOXYLIC ACID CONTAINING FROM ONE TO EIGHT CARBON ATOMS,INCLUSIVE.